1-bromo-4-[chloro(isocyanato)methyl]benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (240 mg, 0.974 mmol) in dichloromethane (2 mL) is added dropwise to a solution of 3-(3-(difluoromethyl)phenyl-amino)cyclopent-2-enone (intermediate 5, 217 mg, 0.974 mmol) in dichloromethane (2 mL) and the reaction mixture is heated at reflux for 2 h. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 159 mg; ESI mass spectrum: [(79Br)-M+H]+=433, [(81Br)-M+H]+=435; Retention time HPLC: 0.56 min (X012_S01). the reaction mixture is heated at reflux for 2 h the phases are extracted twice with dichloromethane The combined organic layers are concentrated the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate) 0.56 min (X012_S01)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (240 mg, 0.974 mmol) in dichloromethane (2 mL) is added dropwise to a solution of 3-(3-(difluoromethyl)phenyl-amino)cyclopent-2-enone (intermediate 5, 217 mg, 0.974 mmol) in dichloromethane (2 mL) and the reaction mixture is heated at reflux for 2 h. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 159 mg; ESI mass spectrum: [(79Br)-M+H]+=433, [(81Br)-M+H]+=435; Retention time HPLC: 0.56 min (X012_S01). the reaction mixture is heated at reflux for 2 h the phases are extracted twice with dichloromethane The combined organic layers are concentrated the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate) 0.56 min (X012_S01)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (14.7 g, 47.6 mmol) in dichloromethane (100 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)-cyclopent-2-enone (11.0 g, 45.6 mmol) in dichloromethane (100 mL) and the mixture is heated at reflux for 1.5 hours. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 7.5 g; ESI mass spectrum: ESI mass spectrum: [(79Br)-M+H]+=451, [(81Br)-M+H]+=453; Retention time HPLC: 1.15 min (V012_S01). the mixture is heated at reflux for 1.5 hours the phases are extracted twice with dichloromethane The combined organic layers are concentrated the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate) 1.15 min (V012_S01)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (14.7 g, 47.6 mmol) in dichloromethane (100 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)-cyclopent-2-enone (11.0 g, 45.6 mmol) in dichloromethane (100 mL) and the mixture is heated at reflux for 1.5 hours. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 7.5 g; ESI mass spectrum: ESI mass spectrum: [(79Br)-M+H]+=451, [(81Br)-M+H]+=453; Retention time HPLC: 1.15 min (V012_S01). the mixture is heated at reflux for 1.5 hours the phases are extracted twice with dichloromethane The combined organic layers are concentrated the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate) 1.15 min (V012_S01)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (400 mg, 1.62 mmol) in dichloromethane (2.5 mL) is added to a solution of 3-(3-(difluoromethyl)phenylamino)-cyclohex-2-enone (intermediate 32, 385 mg, 1.62 mmol) in dichloromethane (2.5 mL). The mixture is heated at reflux for 2 h and cooled to room temperature. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 80:20 to ethyl acetate. Yield: 350 mg; ESI mass spectrum: [(79Br)-M+H]+=447, [(81Br)-M+H]+=449; Retention time HPLC: 0.61 min (X012_S01). The mixture is heated at reflux for 2 h the mixture is extracted twice with dichloromethane The combined organic layers are dried over Na2SO4 concentrated under reduced pressure The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 80:20 to ethyl acetate 0.61 min (X012_S01)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (1.07 g, 4.34 mmol) in dichloromethane (5 mL) is added to a solution of 5-oxo-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-3-enecarboxylic acid (intermediate 22, 1.30 g, 4.34 mmol) in dichloromethane (15 mL) and the mixture is heated at reflux for 3 h. Water and aqueous sodium hydroxide solution are added and the mixture is washed with diethyl ether. The organic layer is discarded and the aqueous layer is acidified with aqueous hydrogen chloride and extracted twice with diethyl ether. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Yield: 770 mg; ESI mass spectrum: [(79Br)-M+H]+=509, [(81Br)-M+H]+=511; Retention time HPLC: 1.25 min, 1.35 min (1:1 mixture of diastereomers) (V001—006). the mixture is heated at reflux for 3 h the mixture is washed with diethyl ether extracted twice with diethyl ether dried over Na2SO4 concentrated under reduced pressure Retention time HPLC: 1.25 min, 1.35 min (1:1 mixture of diastereomers) (V001—006)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (1.07 g, 4.34 mmol) in dichloromethane (5 mL) is added to a solution of 5-oxo-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-3-enecarboxylic acid (intermediate 22, 1.30 g, 4.34 mmol) in dichloromethane (15 mL) and the mixture is heated at reflux for 3 h. Water and aqueous sodium hydroxide solution are added and the mixture is washed with diethyl ether. The organic layer is discarded and the aqueous layer is acidified with aqueous hydrogen chloride and extracted twice with diethyl ether. The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Yield: 770 mg; ESI mass spectrum: [(79Br)-M+H]+=509, [(81Br)-M+H]+=511; Retention time HPLC: 1.25 min, 1.35 min (1:1 mixture of diastereomers) (V001—006). the mixture is heated at reflux for 3 h the mixture is washed with diethyl ether extracted twice with diethyl ether dried over Na2SO4 concentrated under reduced pressure Retention time HPLC: 1.25 min, 1.35 min (1:1 mixture of diastereomers) (V001—006)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (201 mg, 0.815 mmol) in dichloromethane (3 mL) is added to a solution of 5-phenyl-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-2-enone (intermediate 14, 270 mg, 0.815 mmol) in dichloromethane (7 mL), and the mixture is heated at reflux for 4 h and cooled to room temperature. After 2 d the mixture is concentrated under reduced pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 195 mg; ESI mass spectrum: [(79Br)-M+H]+=541, [(81Br)-M+H]+=543; Retention time HPLC: 1.42 min, 1.44 min (1:1 mixture of diastereomers) (Z002—002). the mixture is heated at reflux for 4 h After 2 d the mixture is concentrated under reduced pressure the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40) Retention time HPLC: 1.42 min, 1.44 min (1:1 mixture of diastereomers) (Z002—002)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (201 mg, 0.815 mmol) in dichloromethane (3 mL) is added to a solution of 5-phenyl-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-2-enone (intermediate 14, 270 mg, 0.815 mmol) in dichloromethane (7 mL), and the mixture is heated at reflux for 4 h and cooled to room temperature. After 2 d the mixture is concentrated under reduced pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 195 mg; ESI mass spectrum: [(79Br)-M+H]+=541, [(81Br)-M+H]+=543; Retention time HPLC: 1.42 min, 1.44 min (1:1 mixture of diastereomers) (Z002—002). the mixture is heated at reflux for 4 h After 2 d the mixture is concentrated under reduced pressure the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40) Retention time HPLC: 1.42 min, 1.44 min (1:1 mixture of diastereomers) (Z002—002)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (435 mg, 1.77 mmol) in dichloromethane (5 mL) is added to a solution of 5,5-dimethyl-3-(3-(trifluoromethyl)-phenylamino)cyclohex-2-enone (intermediate 8, 500 mg, 1.77 mmol) in dichloromethane (15 mL) and the mixture is heated at reflux over night. All volatiles are evaporated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 389 mg; ESI mass spectrum: [(79Br)-M+H]+=493, [(81Br)-M+H]+=495; Retention time HPLC: 1.38 min (Z002—002). the mixture is heated at reflux over night All volatiles are evaporated the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40) 1.38 min (Z002—002)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (569 mg, 2.31 mmol) in dichloromethane (5 mL) is added to a solution of 6,6-dimethyl-3-(3-(trifluoromethyl)-phenylamino)cyclohex-2-enone (intermediate 6, 654 mg, 2.31 mmol) in dichloromethane (15 mL), and the resulting mixture is heated at reflux for 4 h and stirred at room temperature over night. Another portion of 1-bromo-4-(chloro(isocyanato)methyl)benzene (283 mg, 1.15 mmol) is added and the mixture is heated at reflux for 24 h. The mixture is cooled to room temperature and all volatiles are evaporated. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 372 mg; ESI mass spectrum: [(79Br)-M+H]+=493, [(81Br)-M+H]+=495; Retention time HPLC: 1.37 min (Z005—001). the resulting mixture is heated at reflux for 4 h the mixture is heated at reflux for 24 h The mixture is cooled to room temperature all volatiles are evaporated The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40) 1.37 min (Z005—001)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (4.25 g, 17.24 mmol) in dichloromethane (30 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)-cyclohex-2-enone (4.00 g, 15.67 mmol) in dichloromethane (60 mL) and the resulting mixture is heated at reflux for 3 h and stirred at room temperature over night. All volatiles are evaporated and the residue is purified by flash chromatography on silica (gradient dichloromethane/methanol 100:0 to 98:2). Yield: 5.10 g; ESI mass spectrum: [(79Br)-M+H]+=465, [(81Br)-M+H]+=467; Retention time HPLC: 1.44 min (V001—006). the resulting mixture is heated at reflux for 3 h All volatiles are evaporated the residue is purified by flash chromatography on silica (gradient dichloromethane/methanol 100:0 to 98:2) 1.44 min (V001—006)